Unsubstituted Oximes as Potential Therapeutic Agents

Abstract

Oximes, which are highly bioactive molecules, have versatile uses in the medical sector and have been indicated to possess biological activity. Certain oximes exist in nature in plants and animals, but they are also obtained by chemical synthesis. Oximes are known for their anti-inflammatory, antimicrobial, antioxidant and anticancer activities. Moreover, they are therapeutic agents against organophosphate (OP) poisoning. Two oximes are already commonly used in therapy. Due to these abilities, new oxime compounds have been synthesized, and their biological activity has been verified. Often, modification of carbonyl compounds into oximes leads to increased activity. Nevertheless, in some cases, oxime activity is connected to the activity of the substrate. Recent works have revealed that new oxime compounds can demonstrate such functions and thus are considered to be potential drugs for pathogenic diseases, as adjuvant therapy in various types of cancer and inflammation and as potential next-generation drugs against OP poisoning.

Full text

symmetry
S
S
Review
Unsubstituted Oximes as Potential
Therapeutic Agents
Alicja K. Surowiak 1, Stanisław Lochy ´nski 1,2 and Daniel J. Strub 1, *
1Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, Wyb.
Wyspia´nskiego 27, 50-370 Wroclaw, Poland; alicja.surowiak@pwr.edu.pl (A.K.S.);
stanislaw.lochynski@pwr.edu.pl (S.L.)
2Institute of Cosmetology, Wroclaw College of Physiotherapy, T. Ko´sciuszki 4, 50-029 Wrocław, Poland
*Correspondence: daniel.strub@pwr.edu.pl; Tel.: +48-71-320-2010
Received: 18 February 2020; Accepted: 24 March 2020; Published: 5 April 2020


Abstract:
Oximes, which are highly bioactive molecules, have versatile uses in the medical sector and
have been indicated to possess biological activity. Certain oximes exist in nature in plants and animals,
but they are also obtained by chemical synthesis. Oximes are known for their anti-inflammatory,
antimicrobial, antioxidant and anticancer activities. Moreover, they are therapeutic agents against
organophosphate (OP) poisoning. Two oximes are already commonly used in therapy. Due to these
abilities, new oxime compounds have been synthesized, and their biological activity has been verified.
Often, modification of carbonyl compounds into oximes leads to increased activity. Nevertheless, in
some cases, oxime activity is connected to the activity of the substrate. Recent works have revealed
that new oxime compounds can demonstrate such functions and thus are considered to be potential
drugs for pathogenic diseases, as adjuvant therapy in various types of cancer and inflammation and
as potential next-generation drugs against OP poisoning.
Keywords: oximes; OP poisoning; antimicrobial; biological activity
1. Introduction
The progressive and rampant development of the world, technological advances, overpopulation
and environmental issues may cause many threats to human health. We are facing serious problems
with a growing number of cancer-related and pathogenic diseases that cannot be effectively treated in
traditional ways. Other detrimental factors are dangers from the development of agriculture, especially
fertilization and the use of pesticides. The exposure to organophosphates (OPs) results in poisoning,
and untreated OPs can lead to death. Obviously, the grand developments in medicine in recent years
are undeniable, but drug alternatives have yet to be sought. Research is largely inspired by substances
that occur in nature. Since 1960s plant oximes are known as one of the precursors of secondary
metabolites in plants both aliphatic and aromatic forms. The majority of oximes are produced by one
of the CYP79 family member—cytochrome P450. All flowering plants possessing CYP79 blueprint are,
theoretically, able to produce oximes. These metabolites are often elements of the protective systems of
plants that act in their defense against herbivores and pests in particular as intermediates in cyanogenic
glycosides formation. Most of plant oximes are excreted as volatiles, only those that are converted
into glycosides are stored in the plant. Oximes of natural origin often possess biological activities.
Their presence in the biological sample might be omitted: oximes are intermediates for biosynthesis
of other metabolites and their concentration is often low. [
1
]. Oximes in animals are, among other
things, part of the olfactory communication between the animals. Oximes occur in nature as elements
of metabolic pathways and are part of the enzymatic oxidation of amino acids and products of its
decarboxylation. Two isomers are possible due to specificity of the C=N double bond; there are two
Symmetry 2020,12, 575; doi:10.3390/sym12040575 www.mdpi.com/journal/symmetry

Symmetry 2020,12, 575 2 of 17
stereoisomeric forms according to the E/Zconfiguration [
2
]. Eisomers of oximes are more biologically
active than Zisomers. Moreover in metabolic processes, certain isomers and a mixture of both forms
are obtained. It is possible that chemical conversion E-isomer to Z-isomer in enzyme catalyzed reaction
takes place [
1
]. During chemical synthesis, both stereoisomers are obtained, most of which can be
separated completely [
3
]. The oxime moiety can be biotransformed, for example, during oxidation
or reduction. The most important property of oximes is their ability to complex with metals, which
makes them suitable for the role of potential therapeutic agents as inhibitors of metalloenzymes [
4
].
Another aspect is the poor water solubility of oximes, but a property that is obligatory to mark a
compound as a potential drug. Therefore, many researchers have modified existing oximes to improve
their water solubility. One such modification has been presented by Okolotowicz et al., who obtained
one amidine-oxime with excellent water solubility (300 mg/mL). Oximes can be formed through a
fusion strategy. Implementing reactive C=O groups and electron pair donator into biomolecules is
also one of oximes features [5]. Moreover, they assume a second- and next generation catalyst role in
bioconjugation [
6
]. The aspect that should be taken under consideration for the application of oximes
as drugs is its cytotoxicity. On the one side cytotoxicity of oximes might cause side effects of certain
therapies, on the other side cytotoxic activity allows one to consider oximes as potential anticancer
agents [
4
]. Many oximes are already known as therapeutic agents. This is why we have decided to
review the recent information about unsubstituted oximes, their anti-inflammatory, antimicrobial,
antioxidant and anticancer activities, and their role against OP poisoning.
2. The Anti-Inflammatory Activity
Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The Park
group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime derivatives
(Figure 1) had a high binding affinity with no suppressive effects. Moreover, nitric oxide (NO)
production was blocked. Many pathophysiological events are associated with production of NO. It is
also a response to proinflammatory cytokines. Moreover both oxime derivatives presented the ability
to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert biological
activity [7].
Symmetry 2020, 12, x FOR PEER REVIEW 2 of 17
specificity of the C=N double bond; there are two stereoisomeric forms according to the E/Z
configuration [2]. E isomers of oximes are more biologically active than Z isomers. Moreover in
metabolic processes, certain isomers and a mixture of both forms are obtained. It is possible that
chemical conversion E-isomer to Z-isomer in enzyme catalyzed reaction takes place [1]. During
chemical synthesis, both stereoisomers are obtained, most of which can be separated completely [3].
The oxime moiety can be biotransformed, for example, during oxidation or reduction. The most
important property of oximes is their ability to complex with metals, which makes them suitable for
the role of potential therapeutic agents as inhibitors of metalloenzymes [4]. Another aspect is the poor
water solubility of oximes, but a property that is obligatory to mark a compound as a potential drug.
Therefore, many researchers have modified existing oximes to improve their water solubility. One
such modification has been presented by Okolotowicz et al., who obtained one amidine-oxime with
excellent water solubility (300 mg/mL). Oximes can be formed through a fusion strategy.
Implementing reactive C=O groups and electron pair donator into biomolecules is also one of oximes
features [5]. Moreover, they assume a second- and next generation catalyst role in bioconjugation [6].
The aspect that should be taken under consideration for the application of oximes as drugs is its
cytotoxicity. On the one side cytotoxicity of oximes might cause side effects of certain therapies, on
the other side cytotoxic activity allows one to consider oximes as potential anticancer agents [4]. Many
oximes are already known as therapeutic agents. This is why we have decided to review the recent
information about unsubstituted oximes, their anti-inflammatory, antimicrobial, antioxidant and
anticancer activities, and their role against OP poisoning.
2. The Anti-Inflammatory Activity
Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The
Park group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime
derivatives (Figure 1) had a high binding affinity with no suppressive effects. Moreover, nitric oxide
(NO) production was blocked. Many pathophysiological events are associated with production of
NO. It is also a response to proinflammatory cytokines. Moreover both oxime derivatives presented
the ability to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert
biological activity [7].
Figure 1. Fluorinated oxime derivatives with the C-16,17-isoxazoline ring system. (a) with methoxy
group and (b) with hydroxyl group.
Additionally, one oxime synthetized by Li was found to be a potent compound in blocking NO
(IC50 = 6.66 µM) and interleukina 6 (IL-6; IC50 = 5.07 µM) production. IL-6 is one of the
proinflammatory cytokines. [8]. The results of the Tharini and Sangeetha study indicate that 3,3-
dimethyl-2,6-dimethylpiperidine-4-one oxime (Figure 2) has severe general anti-inflammatory
activity in contrast to the typical drug dexamethasone [9].
Figure 1.
Fluorinated oxime derivatives with the C-16,17-isoxazoline ring system. (
a
) with methoxy
group and (b) with hydroxyl group.
Additionally, one oxime synthetized by Li was found to be a potent compound in blocking
NO (IC
50
=6.66
µ
M) and interleukina 6 (IL-6; IC
50
=5.07
µ
M) production. IL-6 is one of the
proinflammatory cytokines. [
8
]. The results of the Tharini and Sangeetha study indicate that
3,3-dimethyl-2,6-dimethylpiperidine-4-one oxime (Figure 2) has severe general anti-inflammatory
activity in contrast to the typical drug dexamethasone [9].

Symmetry 2020,12, 575 3 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 2 of 17
specificity of the C=N double bond; there are two stereoisomeric forms according to the E/Z
configuration [2]. E isomers of oximes are more biologically active than Z isomers. Moreover in
metabolic processes, certain isomers and a mixture of both forms are obtained. It is possible that
chemical conversion E-isomer to Z-isomer in enzyme catalyzed reaction takes place [1]. During
chemical synthesis, both stereoisomers are obtained, most of which can be separated completely [3].
The oxime moiety can be biotransformed, for example, during oxidation or reduction. The most
important property of oximes is their ability to complex with metals, which makes them suitable for
the role of potential therapeutic agents as inhibitors of metalloenzymes [4]. Another aspect is the poor
water solubility of oximes, but a property that is obligatory to mark a compound as a potential drug.
Therefore, many researchers have modified existing oximes to improve their water solubility. One
such modification has been presented by Okolotowicz et al., who obtained one amidine-oxime with
excellent water solubility (300 mg/mL). Oximes can be formed through a fusion strategy.
Implementing reactive C=O groups and electron pair donator into biomolecules is also one of oximes
features [5]. Moreover, they assume a second- and next generation catalyst role in bioconjugation [6].
The aspect that should be taken under consideration for the application of oximes as drugs is its
cytotoxicity. On the one side cytotoxicity of oximes might cause side effects of certain therapies, on
the other side cytotoxic activity allows one to consider oximes as potential anticancer agents [4]. Many
oximes are already known as therapeutic agents. This is why we have decided to review the recent
information about unsubstituted oximes, their anti-inflammatory, antimicrobial, antioxidant and
anticancer activities, and their role against OP poisoning.
2. The Anti-Inflammatory Activity
Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The
Park group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime
derivatives (Figure 1) had a high binding affinity with no suppressive effects. Moreover, nitric oxide
(NO) production was blocked. Many pathophysiological events are associated with production of
NO. It is also a response to proinflammatory cytokines. Moreover both oxime derivatives presented
the ability to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert
biological activity [7].
Figure 1. Fluorinated oxime derivatives with the C-16,17-isoxazoline ring system. (a) with methoxy
group and (b) with hydroxyl group.
Additionally, one oxime synthetized by Li was found to be a potent compound in blocking NO
(IC50 = 6.66 µM) and interleukina 6 (IL-6; IC50 = 5.07 µM) production. IL-6 is one of the
proinflammatory cytokines. [8]. The results of the Tharini and Sangeetha study indicate that 3,3-
dimethyl-2,6-dimethylpiperidine-4-one oxime (Figure 2) has severe general anti-inflammatory
activity in contrast to the typical drug dexamethasone [9].
Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime.
Zeferino-Diaz and coworkers recently presented research on oxocholestane oxime diosgenin
derivatives (Figure 3) as potential anti-inflammatory drugs. In
in vivo
studies their compounds
have been indicated to reduce inflammation and edema triggered in mice ear. The expression of
proinflammatory genes such as tumor necrosis factor (TNF-
α
), prostaglandin-endoperoxide synthase 2
(COX-2) and IL-6, with macrophage migration inhibitory factor (MIF) was repressed by the three most
active oximes [10].
Symmetry 2020, 12, x FOR PEER REVIEW 3 of 17
Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime.
Zeferino-Diaz and coworkers recently presented research on oxocholestane oxime diosgenin
derivatives (Figure 3) as potential anti-inflammatory drugs. In in vivo studies their compounds have
been indicated to reduce inflammation and edema triggered in mice ear. The expression of
proinflammatory genes such as tumor necrosis factor (TNF-α), prostaglandin-endoperoxide synthase
2 (COX-2) and IL-6, with macrophage migration inhibitory factor (MIF) was repressed by the three
most active oximes [10].
Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl
group, and (c) ketoxime derivative
In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3′-oxime
(Figure 4) on the inflammatory reaction. They analyzed response to mastitis induced by
lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs).
Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory
factors and reduced inflammatory lesions [11].
Figure 4. 6-Bromoindirubin-3′-oxime.
Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine
serum albumin to examine if protein is protected from denaturation. Both tested ligands (Figure 5)
acquire remarkable anti-inflammatory activity in comparison to diclofenac sodium, achieving values
of IC50 46.76 µM/mL and 55.77 µM/mL respectively [12].
Figure 5. Azo-azomethine based oxime derivatives: (a) with methyl group and (b) with methoxy
group
Hassan et al. presented results of anti-inflammatory activity of various novel quinoline hybrids.
Three of compounds (Figure 6) possessing oxime moiety presented excellent general anti-
inflammatory activity in in vivo studies, using paw edema in rats induced by carrageenan injection,
Figure 3.
Oxocholestane oxime diosgenin derivatives. (
a
) with acetyl group (
b
) with hydroxyl group,
and (c) ketoxime derivative.
In their research Liu and colleagues presented
in vivo
activity of 6-bromoindirubin-3
0
-oxime
(Figure 4) on the inflammatory reaction. They analyzed response to mastitis induced by
lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs).
Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory
factors and reduced inflammatory lesions [11].
Symmetry 2020, 12, x FOR PEER REVIEW 3 of 17
Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime.
Zeferino-Diaz and coworkers recently presented research on oxocholestane oxime diosgenin
derivatives (Figure 3) as potential anti-inflammatory drugs. In in vivo studies their compounds have
been indicated to reduce inflammation and edema triggered in mice ear. The expression of
proinflammatory genes such as tumor necrosis factor (TNF-α), prostaglandin-endoperoxide synthase
2 (COX-2) and IL-6, with macrophage migration inhibitory factor (MIF) was repressed by the three
most active oximes [10].
Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl
group, and (c) ketoxime derivative
In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3′-oxime
(Figure 4) on the inflammatory reaction. They analyzed response to mastitis induced by
lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs).
Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory
factors and reduced inflammatory lesions [11].
Figure 4. 6-Bromoindirubin-3′-oxime.
Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine
serum albumin to examine if protein is protected from denaturation. Both tested ligands (Figure 5)
acquire remarkable anti-inflammatory activity in comparison to diclofenac sodium, achieving values
of IC50 46.76 µM/mL and 55.77 µM/mL respectively [12].
Figure 5. Azo-azomethine based oxime derivatives: (a) with methyl group and (b) with methoxy
group
Hassan et al. presented results of anti-inflammatory activity of various novel quinoline hybrids.
Three of compounds (Figure 6) possessing oxime moiety presented excellent general anti-
inflammatory activity in in vivo studies, using paw edema in rats induced by carrageenan injection,
Figure 4. 6-Bromoindirubin-30-oxime.
Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine serum
albumin to examine if protein is protected from denaturation. Both tested ligands (Figure 5) acquire
remarkable anti-inflammatory activity in comparison to diclofenac sodium, achieving values of IC
50
46.76 µM/mL and 55.77 µM/mL respectively [12].

Symmetry 2020,12, 575 4 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 3 of 17
Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime.
Zeferino-Diaz and coworkers recently presented research on oxocholestane oxime diosgenin
derivatives (Figure 3) as potential anti-inflammatory drugs. In in vivo studies their compounds have
been indicated to reduce inflammation and edema triggered in mice ear. The expression of
proinflammatory genes such as tumor necrosis factor (TNF-α), prostaglandin-endoperoxide synthase
2 (COX-2) and IL-6, with macrophage migration inhibitory factor (MIF) was repressed by the three
most active oximes [10].
Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl
group, and (c) ketoxime derivative
In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3′-oxime
(Figure 4) on the inflammatory reaction. They analyzed response to mastitis induced by
lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs).
Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory
factors and reduced inflammatory lesions [11].
Figure 4. 6-Bromoindirubin-3′-oxime.
Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine
serum albumin to examine if protein is protected from denaturation. Both tested ligands (Figure 5)
acquire remarkable anti-inflammatory activity in comparison to diclofenac sodium, achieving values
of IC50 46.76 µM/mL and 55.77 µM/mL respectively [12].
Figure 5. Azo-azomethine based oxime derivatives: (a) with methyl group and (b) with methoxy
group
Hassan et al. presented results of anti-inflammatory activity of various novel quinoline hybrids.
Three of compounds (Figure 6) possessing oxime moiety presented excellent general anti-
inflammatory activity in in vivo studies, using paw edema in rats induced by carrageenan injection,
Figure 5.
Azo-azomethine based oxime derivatives: (
a
) with methyl group and (
b
) with methoxy group.
Mohassab et al. presented results of anti-inflammatory activity of various novel quinoline hybrids.
Three of compounds (Figure 6) possessing oxime moiety presented excellent general anti-inflammatory
activity in
in vivo
studies, using paw edema in rats induced by carrageenan injection, compared to
indomethacin. Observed percentage of edema inhibition were 100%, 101% and 111% respectively [
13
].
Symmetry 2020, 12, x FOR PEER REVIEW 4 of 17
compared to indomethacin. Observed percentage of edema inhibition were 100%, 101% and 111%
respectively [13].
Figure 6. Quinoline 1,2,4-triazole/oxime derivatives: a) and b) with phenyl group linked to triazole
ring; (c) with allyl group linked to triazole ring (c)
With the same method Abd-Ellah and coworkers tested 1,3,4-oxadiazole/oxime derivatives as a
result on of the hybrids obtained 96.67% reduction in edema[14].
3. The Antimicrobial Activity
Cytotoxicity is one property of oximes; thus, oximes are therapeutic agents for bacterial, fungal
and viral infections. Nocardicin A (Figure 7) is the first β-lactam antibiotic isolated from Nocardia
uniformis [15]. The presence of the oxime moiety in this antibiotic makes it less stable to β-lactamases
[16].
Figure 7. Nocardicin A.
Modification of already existing antibiotics into oximes is a subject that has appeared in research
over the years. Good examples of such modifications are those in cephalosporin antibiotics.
Improvement of water solubility of oximes can be achieved by a modification of oxime moiety by
attaining their ether and ester derivatives. Ceftobiprole medocaril (Figure 8b) is a fifth-generation
cephalosporin antibiotic [17]. Prodrug of ceftobiprole with satisfactory water solubility is shown in
(Figure 8a). It is a β-lactam antibacterial agent from one of the cepham series of cephalosporins. Its
antibacterial activity is connected with the ability to bind to penicillin-binding proteins (PBPs) [18].
Figure 6.
Quinoline 1,2,4-triazole/oxime derivatives: (
a
,
b
) with phenyl group linked to triazole ring;
(c) with allyl group linked to triazole ring (c).
With the same method Abd-Ellah and coworkers tested 1,3,4-oxadiazole/oxime derivatives as a
result on of the hybrids obtained 96.67% reduction in edema [14].
3. The Antimicrobial Activity
Cytotoxicity is one property of oximes; thus, oximes are therapeutic agents for bacterial, fungal
and viral infections. Nocardicin A (Figure 7) is the first
β
-lactam antibiotic isolated from Nocardia
uniformis [
15
]. The presence of the oxime moiety in this antibiotic makes it less stable to
β
-lactamases [
16
].
Symmetry 2020, 12, x FOR PEER REVIEW 4 of 17
compared to indomethacin. Observed percentage of edema inhibition were 100%, 101% and 111%
respectively [13].
Figure 6. Quinoline 1,2,4-triazole/oxime derivatives: a) and b) with phenyl group linked to triazole
ring; (c) with allyl group linked to triazole ring (c)
With the same method Abd-Ellah and coworkers tested 1,3,4-oxadiazole/oxime derivatives as a
result on of the hybrids obtained 96.67% reduction in edema[14].
3. The Antimicrobial Activity
Cytotoxicity is one property of oximes; thus, oximes are therapeutic agents for bacterial, fungal
and viral infections. Nocardicin A (Figure 7) is the first β-lactam antibiotic isolated from Nocardia
uniformis [15]. The presence of the oxime moiety in this antibiotic makes it less stable to β-lactamases
[16].
Figure 7. Nocardicin A.
Modification of already existing antibiotics into oximes is a subject that has appeared in research
over the years. Good examples of such modifications are those in cephalosporin antibiotics.
Improvement of water solubility of oximes can be achieved by a modification of oxime moiety by
attaining their ether and ester derivatives. Ceftobiprole medocaril (Figure 8b) is a fifth-generation
cephalosporin antibiotic [17]. Prodrug of ceftobiprole with satisfactory water solubility is shown in
(Figure 8a). It is a β-lactam antibacterial agent from one of the cepham series of cephalosporins. Its
antibacterial activity is connected with the ability to bind to penicillin-binding proteins (PBPs) [18].
Figure 7. Nocardicin A.
Modification of already existing antibiotics into oximes is a subject that has appeared in
research over the years. Good examples of such modifications are those in cephalosporin antibiotics.

Symmetry 2020,12, 575 5 of 17
Improvement of water solubility of oximes can be achieved by a modification of oxime moiety by
attaining their ether and ester derivatives. Ceftobiprole medocaril (Figure 8b) is a fifth-generation
cephalosporin antibiotic [
17
]. Prodrug of ceftobiprole with satisfactory water solubility is shown in
(Figure 8a). It is a
β
-lactam antibacterial agent from one of the cepham series of cephalosporins. Its
antibacterial activity is connected with the ability to bind to penicillin-binding proteins (PBPs) [18].
Symmetry 2020, 12, x FOR PEER REVIEW 5 of 17
Figure 8. (a) Prodrug of ceftobiprole and (b) ceftobiprole medocaril.
Paulsen and colleagues synthetized (+)-N-6-hydroxyagelasine D, the enantiomer of a well-
known secondary metabolite from marine sponges—(−)-ageloxime D, [19]. The authors revealed that
the previously proposed structures of (-)-ageloxime D extracted from a natural product [20] are in
fact not an oxime, as the spectral data did not match. However, (-)-ageloxime can be obtained by a
basic hydrolysis of agelasine D. (−)-Ageloxime D inhibits biofilm formation from Gram-positive
bacteria Staphylococcus epidermis [19] but is unable to inhibit the growth of planktonic bacteria (MIC
> 45 µM) [20]. Proposed (+)-N-6-hydroxyagelasine D bromide also possesses the ability to reduce
biofilm formation of Staphylococcus epidermidis by 90% at 63 µM [19].
Many antimicrobial active compounds are modified to resemble oximes to increase their activity.
The compound 5,7-dimethoxyflavone carbonyl was modified into an oxime, and this modification
amplified its antifungal functions [21]. In their research, Min et al. synthesized new oxime esters that
had antifungal activity. In addition, they also considered the E, Z stereoisomer substrates of 3-caren-
5-one oxime (Figure 9a,b), which were separated for the first time. Both stereoisomers had relative
inhibition rates above 50% against Physalospora piricola [22].
Figure 8. (a) Prodrug of ceftobiprole and (b) ceftobiprole medocaril.
Paulsen and colleagues synthetized (+)-N-6-hydroxyagelasine D, the enantiomer of a well-known
secondary metabolite from marine sponges—(
−
)-ageloxime D, [
19
]. The authors revealed that the
previously proposed structures of (-)-ageloxime D extracted from a natural product [
20
] are in fact
not an oxime, as the spectral data did not match. However, (-)-ageloxime can be obtained by a basic
hydrolysis of agelasine D. (
−
)-Ageloxime D inhibits biofilm formation from Gram-positive bacteria
Staphylococcus epidermis [
19
] but is unable to inhibit the growth of planktonic bacteria (MIC >45
µ
M) [
20
].
Proposed (+)-N-6-hydroxyagelasine D bromide also possesses the ability to reduce biofilm formation
of Staphylococcus epidermidis by 90% at 63 µM [19].
Many antimicrobial active compounds are modified to resemble oximes to increase their activity.
The compound 5,7-dimethoxyflavone carbonyl was modified into an oxime, and this modification
amplified its antifungal functions [
21
]. In their research, Min et al. synthesized new oxime esters
that had antifungal activity. In addition, they also considered the E, Z stereoisomer substrates of
3-caren-5-one oxime (Figure 9a,b), which were separated for the first time. Both stereoisomers had
relative inhibition rates above 50% against Physalospora piricola [22].

Symmetry 2020,12, 575 6 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 6 of 17
Figure 9. 3-Caren-5-one oximes: E-isomer (a) and Z-isomer (b).
Synthetic naringenin, a flavonoid that naturally occurs in grapefruits, was modified to contain
oximes by Kozłowska et al. Four derivatives have indicated to have antibacterial activity. The
minimal inhibitory concentration (MIC) against Staphylococcus aureus was below 100 µg/mL. Two
oximes (Figure 10) showed MIC values against Staphylococcus aureus and Bacillus subtilis below 12.5
µg/mL [23]. In comparison to naringenin itself, which had no antimicrobial activity, the results
obtained were satisfactory [24].
Figure 9. 3-Caren-5-one oximes: E-isomer (a) and Z-isomer (b).
Synthetic naringenin, a flavonoid that naturally occurs in grapefruits, was modified to contain
oximes by Kozłowska et al. Four derivatives have indicated to have antibacterial activity. The minimal
inhibitory concentration (MIC) against Staphylococcus aureus was below 100
µ
g/mL. Two oximes
(Figure 10) showed MIC values against Staphylococcus aureus and Bacillus subtilis below 12.5
µ
g/mL [
23
].
In comparison to naringenin itself, which had no antimicrobial activity, the results obtained were
satisfactory [24].
Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17
O
OH N
O
OH
O
OH N
O
O
(a)(b)
OH OH
Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,4′-di-O-isopropyl naringenin oxime.
Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial
activity [25]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of
≤128 µg/mL [26] whereas compound (Figure 11a) had a MIC value of 150 µg/mL [27] against B.
subtilis. Similar difference was observed for both of compounds against A. niger obtained MIC values
was 300 µg/mL [27] and ≤256 µg/mL (oxime) [26].
Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime
Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes
on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity.
Oximes (a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b)
presented the best antibacterial activity. Their MIC values were 100 µg/mL [28].
Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime.
The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV-
1) were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the
Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1 activity was displayed by two
compounds (Figure 13), both had low IC50 values of 0.05 and 0.04 µg/mL. Moreover the compounds
shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II
(HSV-2), influenza viruses (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus
(HCV) and Human papillomavirus (HPV) [29].
Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,40-di-O-isopropyl naringenin oxime.
Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial
activity [
25
]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of
≤
128
µ
g/mL [
26
] whereas compound (Figure 11a) had a MIC value of 150
µ
g/mL [
27
] against B. subtilis.
Similar difference was observed for both of compounds against A. niger obtained MIC values was
300 µg/mL [27] and ≤256 µg/mL (oxime) [26].

Symmetry 2020,12, 575 7 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17
O
OH N
O
OH
O
OH N
O
O
(a)(b)
OH OH
Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,4′-di-O-isopropyl naringenin oxime.
Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial
activity [25]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of
≤128 µg/mL [26] whereas compound (Figure 11a) had a MIC value of 150 µg/mL [27] against B.
subtilis. Similar difference was observed for both of compounds against A. niger obtained MIC values
was 300 µg/mL [27] and ≤256 µg/mL (oxime) [26].
Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime
Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes
on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity.
Oximes (a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b)
presented the best antibacterial activity. Their MIC values were 100 µg/mL [28].
Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime.
The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV-
1) were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the
Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1 activity was displayed by two
compounds (Figure 13), both had low IC50 values of 0.05 and 0.04 µg/mL. Moreover the compounds
shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II
(HSV-2), influenza viruses (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus
(HCV) and Human papillomavirus (HPV) [29].
Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime.
Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes
on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity. Oximes
(a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b) presented
the best antibacterial activity. Their MIC values were 100 µg/mL [28].
Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17
O
OH N
O
OH
O
OH N
O
O
(a)(b)
OH OH
Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,4′-di-O-isopropyl naringenin oxime.
Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial
activity [25]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of
≤128 µg/mL [26] whereas compound (Figure 11a) had a MIC value of 150 µg/mL [27] against B.
subtilis. Similar difference was observed for both of compounds against A. niger obtained MIC values
was 300 µg/mL [27] and ≤256 µg/mL (oxime) [26].
Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime
Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes
on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity.
Oximes (a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b)
presented the best antibacterial activity. Their MIC values were 100 µg/mL [28].
Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime.
The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV-
1) were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the
Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1 activity was displayed by two
compounds (Figure 13), both had low IC50 values of 0.05 and 0.04 µg/mL. Moreover the compounds
shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II
(HSV-2), influenza viruses (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus
(HCV) and Human papillomavirus (HPV) [29].
Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime.
The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV-1)
were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the
Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1 activity was displayed by two
compounds (Figure 13), both had low IC
50
values of 0.05 and 0.04
µ
g/mL. Moreover the compounds
shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II
(HSV-2), influenza viruses (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus
(HCV) and Human papillomavirus (HPV) [29].
Symmetry 2020, 12, x FOR PEER REVIEW 8 of 17
N
N
NOH
NH
Cl
N
N
NOH
NH
Cl
H3CO
(a) (b)
Figure 13. (a) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and (b)
(E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime.
Chan et al. tested antiviral activity of indirubin-3′-oxime (Figure 14) by the assessment of the
infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by
about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells.
In the H1N1 treatment of virus–infected macrophages at 24 h post-infection, as well as in infected
ATIs at 48 h post-infection similar results were observed. Additionally, viral matrix 1 protein
expression in H5N1 virus-infected macrophages was effectively suppressed. In vivo studies on mice
have proven that indirubin-3′-oxime does not have a positive effect on survival and does not promote
weight loss, despite that the reduction of expression and secretion of cytokine and chemokine is
observed [30].
Figure 14. Indirubin-3′-oxime.
4. The Antioxidant Activity
In addition to having anti-inflammatory activity, naringenin also revealed antioxidant
properties. The modification of this compound into an oxime increased its antioxidant activity. The
oxime is considered a radioprotector or an anticancer agent [31]. Another example of an oxime with
a high antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times
higher activity than isoxanthohumol, which is comparable to ascorbic acid [32].
Figure 15. Isoxanthohumol oxime.
Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to its
antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have good
radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the IC50
reached 0.31 mg/mL, for the hydroxyl radical the IC50 was 0.23 mg/mL and for the nitric oxide (NO)
radical the IC50 was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value was
196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC50 value of 0.31
Figure 13.
(
a
) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and
(b) (E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime.
Chan et al. tested antiviral activity of indirubin-3
0
-oxime (Figure 14) by the assessment of the
infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by
about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells. In
the H1N1 treatment of virus–infected macrophages at 24 h post-infection, as well as in infected ATIs at
48 h post-infection similar results were observed. Additionally, viral matrix 1 protein expression in

Symmetry 2020,12, 575 8 of 17
H5N1 virus-infected macrophages was effectively suppressed.
In vivo
studies on mice have proven
that indirubin-3
0
-oxime does not have a positive effect on survival and does not promote weight loss,
despite that the reduction of expression and secretion of cytokine and chemokine is observed [30].
Symmetry 2020, 12, x FOR PEER REVIEW 8 of 17
N
N
NOH
NH
Cl
N
N
NOH
NH
Cl
H3CO
(a) (b)
Figure 13. (a) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and (b)
(E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime.
Chan et al. tested antiviral activity of indirubin-3′-oxime (Figure 14) by the assessment of the
infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by
about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells.
In the H1N1 treatment of virus–infected macrophages at 24 h post-infection, as well as in infected
ATIs at 48 h post-infection similar results were observed. Additionally, viral matrix 1 protein
expression in H5N1 virus-infected macrophages was effectively suppressed. In vivo studies on mice
have proven that indirubin-3′-oxime does not have a positive effect on survival and does not promote
weight loss, despite that the reduction of expression and secretion of cytokine and chemokine is
observed [30].
Figure 14. Indirubin-3′-oxime.
4. The Antioxidant Activity
In addition to having anti-inflammatory activity, naringenin also revealed antioxidant
properties. The modification of this compound into an oxime increased its antioxidant activity. The
oxime is considered a radioprotector or an anticancer agent [31]. Another example of an oxime with
a high antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times
higher activity than isoxanthohumol, which is comparable to ascorbic acid [32].
Figure 15. Isoxanthohumol oxime.
Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to its
antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have good
radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the IC50
reached 0.31 mg/mL, for the hydroxyl radical the IC50 was 0.23 mg/mL and for the nitric oxide (NO)
radical the IC50 was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value was
196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC50 value of 0.31
Figure 14. Indirubin-30-oxime.
4. The Antioxidant Activity
In addition to having anti-inflammatory activity, naringenin also revealed antioxidant properties.
The modification of this compound into an oxime increased its antioxidant activity. The oxime is
considered a radioprotector or an anticancer agent [
31
]. Another example of an oxime with a high
antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times higher
activity than isoxanthohumol, which is comparable to ascorbic acid [32].
Symmetry 2020, 12, x FOR PEER REVIEW 8 of 17
N
N
NOH
NH
Cl
N
N
NOH
NH
Cl
H3CO
(a) (b)
Figure 13. (a) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and (b)
(E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime.
Chan et al. tested antiviral activity of indirubin-3′-oxime (Figure 14) by the assessment of the
infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by
about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells.
In the H1N1 treatment of virus–infected macrophages at 24 h post-infection, as well as in infected
ATIs at 48 h post-infection similar results were observed. Additionally, viral matrix 1 protein
expression in H5N1 virus-infected macrophages was effectively suppressed. In vivo studies on mice
have proven that indirubin-3′-oxime does not have a positive effect on survival and does not promote
weight loss, despite that the reduction of expression and secretion of cytokine and chemokine is
observed [30].
Figure 14. Indirubin-3′-oxime.
4. The Antioxidant Activity
In addition to having anti-inflammatory activity, naringenin also revealed antioxidant
properties. The modification of this compound into an oxime increased its antioxidant activity. The
oxime is considered a radioprotector or an anticancer agent [31]. Another example of an oxime with
a high antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times
higher activity than isoxanthohumol, which is comparable to ascorbic acid [32].
Figure 15. Isoxanthohumol oxime.
Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to its
antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have good
radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the IC50
reached 0.31 mg/mL, for the hydroxyl radical the IC50 was 0.23 mg/mL and for the nitric oxide (NO)
radical the IC50 was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value was
196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC50 value of 0.31
Figure 15. Isoxanthohumol oxime.
Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to
its antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have
good radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the
IC
50
reached 0.31 mg/mL, for the hydroxyl radical the IC
50
was 0.23 mg/mL and for the nitric oxide
(NO) radical the IC
50
was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value
was 196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC
50
value
of 0.31 mg/mL [
33
]. Bandeira et al. proved that organotellurium oximes have promising radical
scavenging activity. Against the DPPH radical both compounds presented in Figure 16 had IC
50
values of 5.12
±
0.71 mg/mL and 7.79
±
0.33 mg/mL, respectively. Both oximes have also been
examined for their ability to reduce the 1-n-propyl-tetrazole complex with Fe
3+
(PTZ-Fe
3+
) complex in
2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed
an antioxidant activity similar to that demonstrated by trolox. The first oxime had a capacity of
approximately 8 mM TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of
approximately 7 mM TE/g (ABTS) and 14 mM TE/g (FRAP), which were similar to the control
quercetin [34].

Symmetry 2020,12, 575 9 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17
mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging
activity. Against the DPPH radical both compounds presented in Figure 16 had IC50 values of 5.12 ±
0.71 mg/mL and 7.79 ± 0.33 mg/mL, respectively. Both oximes have also been examined for their
ability to reduce the 1-n-propyl-tetrazole complex with Fe3+(PTZ-Fe3+) complex in 2,2’-azino-bis(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed an antioxidant
activity similar to that demonstrated by trolox. The first oxime had a capacity of approximately 8 mM
TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of approximately 7 mM TE/g
(ABTS) and 14 mM TE/g (FRAP), which were similar to the control quercetin [34].
Figure 16. Tellurium oxime derivatives: (a) 3-butyltellanyl- and (b) 4-butyltellanyl-
Bensegueni et al. presented original work on antioxidant activity of aromatic oximes.
Outstanding results were obtained by one of the oximes (Figure 17). Percentage of DPPH inhibition
was 34.50 ± 1.56. Additionally, in Cupric reducing antioxidant capacity assay (CUPRAC) with an A50
= 2.60 ± 0.16 µg/mL [35].
Figure 17. 1H-indole-3-carbaldehyde oxime.
Siddiqui and colleagues have tested 2,6-diphenylpiperidine-4-one oxime derivatives (Figure 18).
The DPPH activity was tested. Both oximes presented antioxidant activity. Compound (Figure 18b)
presented better activity (IC50+ SEM = 4.53 ± 0.41 µg/mL) than other oxime (IC50 + SEM = 11.13 ± 0.17
µg/mL) [36].
Figure 18. 2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (a) and with hydroxy
and methoxy groups (b)
5. The Anticancer Activity
Pregnenolone is an endogenic steroid and a precursor in the biosynthesis of steroid hormones.
Pregnenolone was modified to a benzylidene oxime and two other. The derivatives were tested for
against cancerous cells: colon (HT-29, HCT-15), central nervous system (SF-295), lungs (HOP-62, A-
549) and breast (MCF-7). All of the derivatives showed promising anticancer properties [37]. The
Figure 16. Tellurium oxime derivatives: (a)3-butyltellanyl- and (b)4-butyltellanyl-.
Bensegueni et al. presented original work on antioxidant activity of aromatic oximes. Outstanding
results were obtained by one of the oximes (Figure 17). Percentage of DPPH inhibition was 34.50
±
1.56. Additionally, in Cupric reducing antioxidant capacity assay (CUPRAC) with an A
50
=2.60
±
0.16 µg/mL [35].
Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17
mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging
activity. Against the DPPH radical both compounds presented in Figure 16 had IC50 values of 5.12 ±
0.71 mg/mL and 7.79 ± 0.33 mg/mL, respectively. Both oximes have also been examined for their
ability to reduce the 1-n-propyl-tetrazole complex with Fe3+(PTZ-Fe3+) complex in 2,2’-azino-bis(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed an antioxidant
activity similar to that demonstrated by trolox. The first oxime had a capacity of approximately 8 mM
TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of approximately 7 mM TE/g
(ABTS) and 14 mM TE/g (FRAP), which were similar to the control quercetin [34].
Figure 16. Tellurium oxime derivatives: (a) 3-butyltellanyl- and (b) 4-butyltellanyl-
Bensegueni et al. presented original work on antioxidant activity of aromatic oximes.
Outstanding results were obtained by one of the oximes (Figure 17). Percentage of DPPH inhibition
was 34.50 ± 1.56. Additionally, in Cupric reducing antioxidant capacity assay (CUPRAC) with an A50
= 2.60 ± 0.16 µg/mL [35].
Figure 17. 1H-indole-3-carbaldehyde oxime.
Siddiqui and colleagues have tested 2,6-diphenylpiperidine-4-one oxime derivatives (Figure 18).
The DPPH activity was tested. Both oximes presented antioxidant activity. Compound (Figure 18b)
presented better activity (IC50+ SEM = 4.53 ± 0.41 µg/mL) than other oxime (IC50 + SEM = 11.13 ± 0.17
µg/mL) [36].
Figure 18. 2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (a) and with hydroxy
and methoxy groups (b)
5. The Anticancer Activity
Pregnenolone is an endogenic steroid and a precursor in the biosynthesis of steroid hormones.
Pregnenolone was modified to a benzylidene oxime and two other. The derivatives were tested for
against cancerous cells: colon (HT-29, HCT-15), central nervous system (SF-295), lungs (HOP-62, A-
549) and breast (MCF-7). All of the derivatives showed promising anticancer properties [37]. The
Figure 17. 1H-indole-3-carbaldehyde oxime.
Siddiqui and colleagues have tested 2,6-diphenylpiperidine-4-one oxime derivatives (Figure 18).
The DPPH activity was tested. Both oximes presented antioxidant activity. Compound (Figure 18b)
presented better activity (IC
50
+SEM =4.53
±
0.41
µ
g/mL) than other oxime (IC
50
+SEM =11.13
±
0.17 µg/mL) [36].
Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17
mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging
activity. Against the DPPH radical both compounds presented in Figure 16 had IC50 values of 5.12 ±
0.71 mg/mL and 7.79 ± 0.33 mg/mL, respectively. Both oximes have also been examined for their
ability to reduce the 1-n-propyl-tetrazole complex with Fe3+(PTZ-Fe3+) complex in 2,2’-azino-bis(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed an antioxidant
activity similar to that demonstrated by trolox. The first oxime had a capacity of approximately 8 mM
TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of approximately 7 mM TE/g
(ABTS) and 14 mM TE/g (FRAP), which were similar to the control quercetin [34].
Figure 16. Tellurium oxime derivatives: (a) 3-butyltellanyl- and (b) 4-butyltellanyl-
Bensegueni et al. presented original work on antioxidant activity of aromatic oximes.
Outstanding results were obtained by one of the oximes (Figure 17). Percentage of DPPH inhibition
was 34.50 ± 1.56. Additionally, in Cupric reducing antioxidant capacity assay (CUPRAC) with an A50
= 2.60 ± 0.16 µg/mL [35].
Figure 17. 1H-indole-3-carbaldehyde oxime.
Siddiqui and colleagues have tested 2,6-diphenylpiperidine-4-one oxime derivatives (Figure 18).
The DPPH activity was tested. Both oximes presented antioxidant activity. Compound (Figure 18b)
presented better activity (IC50+ SEM = 4.53 ± 0.41 µg/mL) than other oxime (IC50 + SEM = 11.13 ± 0.17
µg/mL) [36].
Figure 18. 2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (a) and with hydroxy
and methoxy groups (b)
5. The Anticancer Activity
Pregnenolone is an endogenic steroid and a precursor in the biosynthesis of steroid hormones.
Pregnenolone was modified to a benzylidene oxime and two other. The derivatives were tested for
against cancerous cells: colon (HT-29, HCT-15), central nervous system (SF-295), lungs (HOP-62, A-
549) and breast (MCF-7). All of the derivatives showed promising anticancer properties [37]. The
Figure 18.
2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (
a
) and with hydroxy
and methoxy groups (b).
5. The Anticancer Activity
Pregnenolone is an endogenic steroid and a precursor in the biosynthesis of steroid hormones.
Pregnenolone was modified to a benzylidene oxime and two other. The derivatives were tested for
against cancerous cells: colon (HT-29, HCT-15), central nervous system (SF-295), lungs (HOP-62, A-549)
and breast (MCF-7). All of the derivatives showed promising anticancer properties [
37
]. The oxime
presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle and it also
suppresses tumor growth. It was tested in liver cells (Hep G2) [38].

Symmetry 2020,12, 575 10 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 10 of 17
oxime presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle
and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38].
Figure 19. Indirubin 3′oxime.
Other oximes that display anticancer activity are alkannin and shikonin derivatives. These
modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562
leukemia cells [39].
N
NOMe
OMe
HO
HO O
N
NOMe
OMe
HO
HO
O
O
O
(a) (b)
Figure 20. (a) Shikonin and (b) alkannin oxime derivatives.
Qin et al. prepared oxime derivatives of α,β-unsaturated tetralone. All synthetized compounds
were tested on its antiproliferative activity on human cancer cells: PC-3, HT-29, MCF-7, H-460, A-549,
PaCa-2 and PANC-1. The most active compounds were then assessed for their mechanistic effects on
the EGF receptor (EGFR) tyrosine kinase (TK), BRAFV600E gene mutation and tubulin polymerization.
In vitro studies were carried out in order to determine the potential of reversion of the efflux-
mediated resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active.
Figure 21. Oxime derivatives of α,β-unsaturated tetralone: (a) chlorinated, (b) brominated; and (c)
dibrominated and multimethoxy derivative.
Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c)
against the PANC-1, A-549, PaCa-2 and PC-3 cell lines, achieving IC50 value of 0.02 µM. Another
compound (Figure 21a) inhibited the BRAFV600E gene mutation with an IC50 value of 0.9 µM. One of
the oxime analogs (Figure 21c) presented excellent inhibitory activity to EGFR TK (IC50 of 0.07 µM).
Moreover, all three compounds have been indicated to have dual roles as anticancer agents and MDR
(multidrug resistance) reversal agents [40]. Additionally, Kozłowska et al. evaluated the cytotoxicity
of naringenin derivatives in the human colon adenocarcinoma HT-29 cell line. The incorporation of
the oxime group into one of the compounds allowed this compound to become a highly potent
antiproliferative agent from a nonactive substrate. The oxime (Figure 10b) had an IC50 = 4.59 ± 0.56
µg/mL. Further, three other oximes revealed decreased IC50 value compared to the positive control,
Figure 19. Indirubin 30oxime.
Other oximes that display anticancer activity are alkannin and shikonin derivatives. These
modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562 leukemia
cells [39].
Symmetry 2020, 12, x FOR PEER REVIEW 10 of 17
oxime presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle
and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38].
Figure 19. Indirubin 3′oxime.
Other oximes that display anticancer activity are alkannin and shikonin derivatives. These
modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562
leukemia cells [39].
N
NOMe
OMe
HO
HO O
N
NOMe
OMe
HO
HO
O
O
O
(a) (b)
Figure 20. (a) Shikonin and (b) alkannin oxime derivatives.
Qin et al. prepared oxime derivatives of α,β-unsaturated tetralone. All synthetized compounds
were tested on its antiproliferative activity on human cancer cells: PC-3, HT-29, MCF-7, H-460, A-549,
PaCa-2 and PANC-1. The most active compounds were then assessed for their mechanistic effects on
the EGF receptor (EGFR) tyrosine kinase (TK), BRAFV600E gene mutation and tubulin polymerization.
In vitro studies were carried out in order to determine the potential of reversion of the efflux-
mediated resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active.
Figure 21. Oxime derivatives of α,β-unsaturated tetralone: (a) chlorinated, (b) brominated; and (c)
dibrominated and multimethoxy derivative.
Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c)
against the PANC-1, A-549, PaCa-2 and PC-3 cell lines, achieving IC50 value of 0.02 µM. Another
compound (Figure 21a) inhibited the BRAFV600E gene mutation with an IC50 value of 0.9 µM. One of
the oxime analogs (Figure 21c) presented excellent inhibitory activity to EGFR TK (IC50 of 0.07 µM).
Moreover, all three compounds have been indicated to have dual roles as anticancer agents and MDR
(multidrug resistance) reversal agents [40]. Additionally, Kozłowska et al. evaluated the cytotoxicity
of naringenin derivatives in the human colon adenocarcinoma HT-29 cell line. The incorporation of
the oxime group into one of the compounds allowed this compound to become a highly potent
antiproliferative agent from a nonactive substrate. The oxime (Figure 10b) had an IC50 = 4.59 ± 0.56
µg/mL. Further, three other oximes revealed decreased IC50 value compared to the positive control,
Figure 20. (a) Shikonin and (b) alkannin oxime derivatives.
Qin et al. prepared oxime derivatives of
α
,
β
-unsaturated tetralone. All synthetized compounds
were tested on its antiproliferative activity on human cancer cells: PC-3, HT-29, MCF-7, H-460, A-549,
PaCa-2 and PANC-1. The most active compounds were then assessed for their mechanistic effects on
the EGF receptor (EGFR) tyrosine kinase (TK), BRAF
V600E
gene mutation and tubulin polymerization.
In vitro
studies were carried out in order to determine the potential of reversion of the efflux-mediated
resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active.
Symmetry 2020, 12, x FOR PEER REVIEW 10 of 17
oxime presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle
and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38].
Figure 19. Indirubin 3′oxime.
Other oximes that display anticancer activity are alkannin and shikonin derivatives. These
modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562
leukemia cells [39].
N
NOMe
OMe
HO
HO O
N
NOMe
OMe
HO
HO
O
O
O
(a) (b)
Figure 20. (a) Shikonin and (b) alkannin oxime derivatives.
Qin et al. prepared oxime derivatives of α,β-unsaturated tetralone. All synthetized compounds
were tested on its antiproliferative activity on human cancer cells: PC-3, HT-29, MCF-7, H-460, A-549,
PaCa-2 and PANC-1. The most active compounds were then assessed for their mechanistic effects on
the EGF receptor (EGFR) tyrosine kinase (TK), BRAFV600E gene mutation and tubulin polymerization.
In vitro studies were carried out in order to determine the potential of reversion of the efflux-
mediated resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active.
Figure 21. Oxime derivatives of α,β-unsaturated tetralone: (a) chlorinated, (b) brominated; and (c)
dibrominated and multimethoxy derivative.
Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c)
against the PANC-1, A-549, PaCa-2 and PC-3 cell lines, achieving IC50 value of 0.02 µM. Another
compound (Figure 21a) inhibited the BRAFV600E gene mutation with an IC50 value of 0.9 µM. One of
the oxime analogs (Figure 21c) presented excellent inhibitory activity to EGFR TK (IC50 of 0.07 µM).
Moreover, all three compounds have been indicated to have dual roles as anticancer agents and MDR
(multidrug resistance) reversal agents [40]. Additionally, Kozłowska et al. evaluated the cytotoxicity
of naringenin derivatives in the human colon adenocarcinoma HT-29 cell line. The incorporation of
the oxime group into one of the compounds allowed this compound to become a highly potent
antiproliferative agent from a nonactive substrate. The oxime (Figure 10b) had an IC50 = 4.59 ± 0.56
µg/mL. Further, three other oximes revealed decreased IC50 value compared to the positive control,
Figure 21.
Oxime derivatives of
α
,
β
-unsaturated tetralone: (
a
) chlorinated, (
b
) brominated; and
(c) dibrominated and multimethoxy derivative.
Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c)
against the PANC-1, A-549, PaCa-2 and PC-3 cell lines, achieving IC
50
value of 0.02
µ
M. Another
compound (Figure 21a) inhibited the BRAF
V600E
gene mutation with an IC
50
value of 0.9
µ
M. One of
the oxime analogs (Figure 21c) presented excellent inhibitory activity to EGFR TK (IC
50
of 0.07
µ
M).
Moreover, all three compounds have been indicated to have dual roles as anticancer agents and MDR
(multidrug resistance) reversal agents [
40
]. Additionally, Kozłowska et al. evaluated the cytotoxicity
of naringenin derivatives in the human colon adenocarcinoma HT-29 cell line. The incorporation
of the oxime group into one of the compounds allowed this compound to become a highly potent
antiproliferative agent from a nonactive substrate. The oxime (Figure 10b) had an IC
50
=4.59
±
0.56
µ
g/mL. Further, three other oximes revealed decreased IC
50
value compared to the positive control,

Symmetry 2020,12, 575 11 of 17
cisplatin and were a bit weaker than the cytostatic antibiotic, doxorubicin [
23
]. Zha et al. synthesized
α
,
β
-unsaturated carbonyl-based oximes containing ligustrazine moiety. Those compounds strongly
inhibited growth of five cancer cell types, A-549, PC-3, MCF-7, PaCa-2 and HT-29. The best activity, as
an inhibitor of tubulin polymerization, BRAF
V600E
, focal adhesion kinase (FAK) and EGFR-TK, was
displayed by the oxime shown in Figure 22 [41].
Symmetry 2020, 12, x FOR PEER REVIEW 11 of 17
cisplatin and were a bit weaker than the cytostatic antibiotic, doxorubicin [23]. Zha et al. synthesized
α,β-unsaturated carbonyl-based oximes containing ligustrazine moiety. Those compounds strongly
inhibited growth of five cancer cell types, A-549, PC-3, MCF-7, PaCa-2 and HT-29. The best activity,
as an inhibitor of tubulin polymerization, BRAFV600E, focal adhesion kinase (FAK) and EGFR-TK, was
displayed by the oxime shown in Figure 22 [41].
Figure 22. α,β-unsaturated carbonyl based oxime with ligustrazine moiety.
Often, oximes are more polar than their baseline molecules [42]. Griseofulvin oxime derivatives
proved to have improved anticancer activity than the baseline molecule. Presence of the oxime
moiety at the 4′ position improved the potency 2-fold to 12 µM [43].
6. A counteractive Agent to Organophosphorus Compound Poisoning
Poisoning from organophosphorus (OP) compounds is a very large therapeutic problem,
especially from pesticides and substances that pose serious danger to the nervous system. Treating
of OP-poisoning depends on the type of nerve agent, which can distinguish the G-type and V-type
according to volatility [44]. Additionally it is proven that the location of the oxime moiety is the most
important for the capacity of reversing different OP inhibitors effect [45]. There are two therapeutic
agents used in OP poisoning: pralidoxime and obidoxime (Figure 23a,b), which are applied as
reactivators of OP-inhibited acetylcholinesterase (AChE) in the presence of reversible antagonists of
a muscarinic receptor, such as, for example, atropine [44]. Recently, pralidoxime was tested in vivo
for its tissue and blood distribution profiles in nonintoxicated rats. The considerable uptake was
observed in the kidney and quite lower rates were observed in the liver, lung and heart, with lesser
amounts in the brain and blood [46]. Another three promising oxime drugs are asoxime dichloride,
trimedoxime dibromide and methoximedichloride, which were synthesized in the previous century
[44]. Wilhelm et al. tested reactivators on OP-poisoned guinea pigs. Methoximedichloride is
efficacious against broad spectrum of OP (soman, tabun, cyclosarin, sarin and VX, and the
chlorpyrifos oxon, pesticides paraoxon and phorate oxon) in case of 24-h survivability in equimolar
dose (146 µmol/kg). Asoxime dichloride was also active but on the second tier, trimedoxime
dibromide as the toxic compound was tested in a dose of 35 µmol/kg and offered survival protection
between the second and third tier [47]. Costa et al. proposed two new oximes (Figure 23c,d) to
reactivate human AChE and butyrylcholinesterase (BChE) that has been inhibited by
organophosphate compounds, mainly the inhibitory activity of three OPs: chlorpyrifos, diazinon and
malathion [48]. Unfortunately, oximes are mostly useless against soman poisoning [49].
Figure 22. α,β-unsaturated carbonyl based oxime with ligustrazine moiety.
Often, oximes are more polar than their baseline molecules [
42
]. Griseofulvin oxime derivatives
proved to have improved anticancer activity than the baseline molecule. Presence of the oxime moiety
at the 40position improved the potency 2-fold to 12 µM [43].
6. A Counteractive Agent to Organophosphorus Compound Poisoning
Poisoning from organophosphorus (OP) compounds is a very large therapeutic problem, especially
from pesticides and substances that pose serious danger to the nervous system. Treating of OP-poisoning
depends on the type of nerve agent, which can distinguish the G-type and V-type according to
volatility [
44
]. Additionally it is proven that the location of the oxime moiety is the most important
for the capacity of reversing different OP inhibitors effect [
45
]. There are two therapeutic agents used
in OP poisoning: pralidoxime and obidoxime (Figure 23a,b), which are applied as reactivators of
OP-inhibited acetylcholinesterase (AChE) in the presence of reversible antagonists of a muscarinic
receptor, such as, for example, atropine [
44
]. Recently, pralidoxime was tested
in vivo
for its tissue and
blood distribution profiles in nonintoxicated rats. The considerable uptake was observed in the kidney
and quite lower rates were observed in the liver, lung and heart, with lesser amounts in the brain and
blood [
46
]. Another three promising oxime drugs are asoxime dichloride, trimedoxime dibromide
and methoximedichloride, which were synthesized in the previous century [
44
]. Wilhelm et al. tested
reactivators on OP-poisoned guinea pigs. Methoximedichloride is efficacious against broad spectrum
of OP (soman, tabun, cyclosarin, sarin and VX, and the chlorpyrifos oxon, pesticides paraoxon and
phorate oxon) in case of 24-h survivability in equimolar dose (146
µ
mol/kg). Asoxime dichloride was
also active but on the second tier, trimedoxime dibromide as the toxic compound was tested in a
dose of 35
µ
mol/kg and offered survival protection between the second and third tier [
47
]. Costa et al.
proposed two new oximes (Figure 23c,d) to reactivate human AChE and butyrylcholinesterase (BChE)
that has been inhibited by organophosphate compounds, mainly the inhibitory activity of three OPs:
chlorpyrifos, diazinon and malathion [
48
]. Unfortunately, oximes are mostly useless against soman
poisoning [49].

Symmetry 2020,12, 575 12 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 12 of 17
Figure 23. (a) Pralidoxime; (b) obidoxime; (c) (E)-2-((E)-3-(hydroxyimino)butan-2-
ylidene)hydrazinecarbothioamide and (d) (2E,3E)-3-(2-phenylhydrazono)butan-2-one oxime.
The oxime presented in Figure 23c reached a percent (%) reactivation ± SEM at a concentration
of 1 µM of 10 ± 0.016, and in Figure 23d showed a value of 7 ± 0.009 against chlorpyrifos. The oxime
presented in Figure 23b had a percent (%) reactivation ± SEM at a concentration of 1 µM of 20 ± 0.010,
and shown in Figure 23b oxime 2 showed a value of 12 ± 0.025 against the second OP. The oxime
presented in Figure 23d had percent (%) reactivation ± SEM at a concentration of 1 µM of 5 ± 0.012,
and the oxime shown in Figure 23d showed a value of 12 ± 0.019 against the third OP. The oximes
shown in Figure 23c,d had similar activity to pralidoxime: oxime (Figure 23c) had the same percent
reactivation against diazinon poisoning as obidoxime [48]. Žunec et al. presented their in vivo
research on new therapeutic agents against paraoxon poisoning. Two oximes presented in Figure 24,
stood out for their low acute toxicities and excellent antidotal effects.
Figure 24. Bispyridinium oxime derivatives: with propyl linker (a) and butyl linker (b)
Oximes have been applied in male mice in the amount of 5% of their lethal dose (LD50) and
combined with atropine, resulting in a protection index (PI) of 74.1 and 100, respectively. Moreover,
the use of these combinations increased the survival of all animals up to 63.0 of the LD50 of paraoxon.
Both oximes might be good antidotes for OP poisoning. Moreover, both monoximes are the least toxic
among all tested. The LD50 of oxime presented in Figure 24a was 672.8 mg/kg [50]. Kuca et al.
presented their research results on trisquarternary bisoxime as a potential drug against OP poisoning.
Unfortunately, it cannot be considered an AChE reactivator because the rate of reactivation of AChE
was worse than for standard reactivators. The oxime shown in Figure 25 has indicated to reactivate
AChE after inhibition by sarin and agent VX with a percent reactivation above 20% at high
concentrations (10-3 M). Moreover, this compound will not penetrate the blood–brain barrier due to
three positive charges. However, the high hydrophilicity and relatively large size of the studied
bisoxime reactivator makes it an interesting candidate for BChE pseudocatalytic reactivation [51].
Figure 23.
(
a
) Pralidoxime; (
b
) obidoxime; (
c
)(E)-2-((E)-3-(hydroxyimino)butan-2-ylidene)hydrazinecarboth
ioamide and (d) (2E,3E)-3-(2-phenylhydrazono)butan-2-one oxime.
The oxime presented in Figure 23c reached a percent (%) reactivation
±
SEM at a concentration of
1
µ
M of 10
±
0.016, and in Figure 23d showed a value of 7
±
0.009 against chlorpyrifos. The oxime
presented in Figure 23b had a percent (%) reactivation
±
SEM at a concentration of 1
µ
M of 20
±
0.010,
and shown in Figure 23b oxime 2 showed a value of 12
±
0.025 against the second OP. The oxime
presented in Figure 23d had percent (%) reactivation
±
SEM at a concentration of 1
µ
M of 5
±
0.012, and
the oxime shown in Figure 23d showed a value of 12
±
0.019 against the third OP. The oximes shown in
Figure 23c,d had similar activity to pralidoxime: oxime (Figure 23c) had the same percent reactivation
against diazinon poisoning as obidoxime [
48
]. Žunec et al. presented their
in vivo
research on new
therapeutic agents against paraoxon poisoning. Two oximes presented in Figure 24, stood out for their
low acute toxicities and excellent antidotal effects.
Symmetry 2020, 12, x FOR PEER REVIEW 12 of 17
Figure 23. (a) Pralidoxime; (b) obidoxime; (c) (E)-2-((E)-3-(hydroxyimino)butan-2-
ylidene)hydrazinecarbothioamide and (d) (2E,3E)-3-(2-phenylhydrazono)butan-2-one oxime.
The oxime presented in Figure 23c reached a percent (%) reactivation ± SEM at a concentration
of 1 µM of 10 ± 0.016, and in Figure 23d showed a value of 7 ± 0.009 against chlorpyrifos. The oxime
presented in Figure 23b had a percent (%) reactivation ± SEM at a concentration of 1 µM of 20 ± 0.010,
and shown in Figure 23b oxime 2 showed a value of 12 ± 0.025 against the second OP. The oxime
presented in Figure 23d had percent (%) reactivation ± SEM at a concentration of 1 µM of 5 ± 0.012,
and the oxime shown in Figure 23d showed a value of 12 ± 0.019 against the third OP. The oximes
shown in Figure 23c,d had similar activity to pralidoxime: oxime (Figure 23c) had the same percent
reactivation against diazinon poisoning as obidoxime [48]. Žunec et al. presented their in vivo
research on new therapeutic agents against paraoxon poisoning. Two oximes presented in Figure 24,
stood out for their low acute toxicities and excellent antidotal effects.
Figure 24. Bispyridinium oxime derivatives: with propyl linker (a) and butyl linker (b)
Oximes have been applied in male mice in the amount of 5% of their lethal dose (LD50) and
combined with atropine, resulting in a protection index (PI) of 74.1 and 100, respectively. Moreover,
the use of these combinations increased the survival of all animals up to 63.0 of the LD50 of paraoxon.
Both oximes might be good antidotes for OP poisoning. Moreover, both monoximes are the least toxic
among all tested. The LD50 of oxime presented in Figure 24a was 672.8 mg/kg [50]. Kuca et al.
presented their research results on trisquarternary bisoxime as a potential drug against OP poisoning.
Unfortunately, it cannot be considered an AChE reactivator because the rate of reactivation of AChE
was worse than for standard reactivators. The oxime shown in Figure 25 has indicated to reactivate
AChE after inhibition by sarin and agent VX with a percent reactivation above 20% at high
concentrations (10-3 M). Moreover, this compound will not penetrate the blood–brain barrier due to
three positive charges. However, the high hydrophilicity and relatively large size of the studied
bisoxime reactivator makes it an interesting candidate for BChE pseudocatalytic reactivation [51].
Figure 24. Bispyridinium oxime derivatives: with propyl linker (a) and butyl linker (b).
Oximes have been applied in male mice in the amount of 5% of their lethal dose (LD
50
) and
combined with atropine, resulting in a protection index (PI) of 74.1 and 100, respectively. Moreover, the
use of these combinations increased the survival of all animals up to 63.0 of the LD
50
of paraoxon. Both
oximes might be good antidotes for OP poisoning. Moreover, both monoximes are the least toxic among
all tested. The LD
50
of oxime presented in Figure 24a was 672.8 mg/kg [
50
]. Kuca et al. presented their
research results on trisquarternary bisoxime as a potential drug against OP poisoning. Unfortunately, it
cannot be considered an AChE reactivator because the rate of reactivation of AChE was worse than for
standard reactivators. The oxime shown in Figure 25 has indicated to reactivate AChE after inhibition
by sarin and agent VX with a percent reactivation above 20% at high concentrations (10-3 M). Moreover,
this compound will not penetrate the blood–brain barrier due to three positive charges. However, the
high hydrophilicity and relatively large size of the studied bisoxime reactivator makes it an interesting
candidate for BChE pseudocatalytic reactivation [51].

Symmetry 2020,12, 575 13 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 13 of 17
Figure 25. (E)-1,1’-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)-
(hydroxyimino)methyl)pyridin-1-ium).
Another approach was presented by Santoni and colleagues. They synthesized a
tetrahydroacridine linked to the non-quaternary oxime reactivator presented in Figure 26 and a
chlorinated derivative. Both molecules proved to have excellent nerve agent antidote efficacy (kr2
reactivation), better than the well-known drug obidoxime against three OPs: agent VX, sarin and
paraoxon [52].
Figure 26. Tetrahydroacridine based oxime.
Zorbaz et al. presented two oximes (Figure 27a,b) that proved to have notable potential in
cyclosarin poisoning especially in reversing hBChE blockage. Moreover, both oximes have been
predicted to cross the blood-brain barrier at satisfactory levels. [53].
Figure 27. Hydroxypiridine oxime derivatives: with pentyl (a) and heptyl (b) linker
An active compound able to reverse OP poisoning was presented by Kovarik et al. The best
results in the in vivo study were obtained against agent VX and paraoxon. The compound shown in
Figure 28 proved to have the greatest antidotal potential with a PI above 10 and ensured mouse
survival against 10× the LD50. Moreover, this oxime proved to have a better PI against tabun
poisoning than the other commonly known drug, trimedoxime bromide. No significant cytotoxicity
was observed [54].
Figure 25.
(E)-1,1
0
-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)-(hydroxyimino)methyl)pyridin-1-ium).
Another approach was presented by Santoni and colleagues. They synthesized a tetrahydroacridine
linked to the non-quaternary oxime reactivator presented in Figure 26 and a chlorinated derivative.
Both molecules proved to have excellent nerve agent antidote efficacy (kr2 reactivation), better than
the well-known drug obidoxime against three OPs: agent VX, sarin and paraoxon [52].
Symmetry 2020, 12, x FOR PEER REVIEW 13 of 17
Figure 25. (E)-1,1’-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)-
(hydroxyimino)methyl)pyridin-1-ium).
Another approach was presented by Santoni and colleagues. They synthesized a
tetrahydroacridine linked to the non-quaternary oxime reactivator presented in Figure 26 and a
chlorinated derivative. Both molecules proved to have excellent nerve agent antidote efficacy (kr2
reactivation), better than the well-known drug obidoxime against three OPs: agent VX, sarin and
paraoxon [52].
Figure 26. Tetrahydroacridine based oxime.
Zorbaz et al. presented two oximes (Figure 27a,b) that proved to have notable potential in
cyclosarin poisoning especially in reversing hBChE blockage. Moreover, both oximes have been
predicted to cross the blood-brain barrier at satisfactory levels. [53].
Figure 27. Hydroxypiridine oxime derivatives: with pentyl (a) and heptyl (b) linker
An active compound able to reverse OP poisoning was presented by Kovarik et al. The best
results in the in vivo study were obtained against agent VX and paraoxon. The compound shown in
Figure 28 proved to have the greatest antidotal potential with a PI above 10 and ensured mouse
survival against 10× the LD50. Moreover, this oxime proved to have a better PI against tabun
poisoning than the other commonly known drug, trimedoxime bromide. No significant cytotoxicity
was observed [54].
Figure 26. Tetrahydroacridine based oxime.
Zorbaz et al. presented two oximes (Figure 27a,b) that proved to have notable potential in
cyclosarin poisoning especially in reversing hBChE blockage. Moreover, both oximes have been
predicted to cross the blood-brain barrier at satisfactory levels. [53].
Symmetry 2020, 12, x FOR PEER REVIEW 13 of 17
Figure 25. (E)-1,1’-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)-
(hydroxyimino)methyl)pyridin-1-ium).
Another approach was presented by Santoni and colleagues. They synthesized a
tetrahydroacridine linked to the non-quaternary oxime reactivator presented in Figure 26 and a
chlorinated derivative. Both molecules proved to have excellent nerve agent antidote efficacy (kr2
reactivation), better than the well-known drug obidoxime against three OPs: agent VX, sarin and
paraoxon [52].
Figure 26. Tetrahydroacridine based oxime.
Zorbaz et al. presented two oximes (Figure 27a,b) that proved to have notable potential in
cyclosarin poisoning especially in reversing hBChE blockage. Moreover, both oximes have been
predicted to cross the blood-brain barrier at satisfactory levels. [53].
Figure 27. Hydroxypiridine oxime derivatives: with pentyl (a) and heptyl (b) linker
An active compound able to reverse OP poisoning was presented by Kovarik et al. The best
results in the in vivo study were obtained against agent VX and paraoxon. The compound shown in
Figure 28 proved to have the greatest antidotal potential with a PI above 10 and ensured mouse
survival against 10× the LD50. Moreover, this oxime proved to have a better PI against tabun
poisoning than the other commonly known drug, trimedoxime bromide. No significant cytotoxicity
was observed [54].
Figure 27. Hydroxypiridine oxime derivatives: with pentyl (a) and heptyl (b) linker.
An active compound able to reverse OP poisoning was presented by Kovarik et al. The best results
in the
in vivo
study were obtained against agent VX and paraoxon. The compound shown in Figure 28
proved to have the greatest antidotal potential with a PI above 10 and ensured mouse survival against
10
×
the LD
50
. Moreover, this oxime proved to have a better PI against tabun poisoning than the other
commonly known drug, trimedoxime bromide. No significant cytotoxicity was observed [54].

Symmetry 2020,12, 575 14 of 17
Symmetry 2020, 12, x FOR PEER REVIEW 14 of 17
Figure 28. Triazol oxime derivative.
7. Conclusions
In conclusion, oximes were indicated to have a therapeutic potential. Some have already been
used as drugs for OP poisoning and antibiotics. Many newly synthesized oximes have shown
promising properties, such as antimicrobial, anti-inflammatory, antioxidant, anticancer and against
OP poisoning. Consequently, further studies on oximes and their biological activities should be
undertaken to determine more active agents that might be considered as effective drugs.
Funding: This work was supported by the project: “Synthesis of new fragrances from raw materials of a natural
origin with applications in perfumery, cosmetics and household chemistry” (SYNFRA; LIDER Program,
LIDER/4/0099/L-7/15/NCBR/2016), which was financed by the National Centre for Research and Development—
Poland.
Conflicts of Interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.
The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the
writing of the manuscript, or in the decision to publish the results.
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Figure 28. Triazol oxime derivative.
7. Conclusions
In conclusion, oximes were indicated to have a therapeutic potential. Some have already been used
as drugs for OP poisoning and antibiotics. Many newly synthesized oximes have shown promising
properties, such as antimicrobial, anti-inflammatory, antioxidant, anticancer and against OP poisoning.
Consequently, further studies on oximes and their biological activities should be undertaken to
determine more active agents that might be considered as effective drugs.
Funding:
This work was supported by the project: “Synthesis of new fragrances from raw materials of
a natural origin with applications in perfumery, cosmetics and household chemistry” (SYNFRA; LIDER
Program, LIDER/4/0099/L-7/15/NCBR/2016), which was financed by the National Centre for Research
and Development—Poland.
Conflicts of Interest:
On behalf of all authors, the corresponding author states that there is no conflict of interest.
The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the
writing of the manuscript, or in the decision to publish the results.
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